Decoding the biology of prostate cancer

International research team receives $14 million to study mechanisms of prostate-cancer prevention

March 2, 2006

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By LISA HAYWARD FOLK

Dr. John Crowley, Phyllis Goodman (center) and Dr. Cathy Tangen, of the Center's Southwest Oncology Group, are members of an international team studying data collected from participants in the Prostate Cancer Prevention Trial. They are working to identify behavioral, metabolic and genetic determinants of prostate-cancer risk and to determine the best use of the prostate-cancer drug finasteride.

Photo by Dean Forbes

Prostate cancer is an unpredictable adversary. The second deadliest male cancer takes many forms in the hundreds of thousands of people it afflicts — sometimes fast-growing and lethal, sometimes inert and benign. Because of the disease's variable nature, screening and/or treatment for prostate cancer may not suit all patients.

Almost three years ago, the Hutchinson Center's Public Health Sciences Division's Southwest Oncology Group (SWOG) published the complex results from the Prostate Cancer Prevention Trial (PCPT). The study found that the drug finasteride cut the chance of developing prostate cancer by nearly 25 percent, but also increased the chance of developing a subgroup of clinically significant high-grade cancers by 25 percent.

Five-year project grant

With the aim of better understanding these results, a research team comprised of more than 20 scientists and statisticians from across the United States, Canada and Australia is conducting a five-year Program Project Grant, or PO-1. The study — funded by $14 million from the National Cancer Institute — is analyzing specimens of serum, DNA, prostate biopsy and surgery tissue taken from PCPT participants to generate insights into the molecular biology of prostate cancer.

Dr. Alan Kristal, of the PHS Cancer Prevention Program, and Dr. Scott Lippman, of the University of Texas M.D. Anderson Cancer Center in Houston, lead the group. Their goal is to identify behavioral, metabolic and genetic determinants of prostate-cancer risk, and to determine when and how to best use finasteride for prostate-cancer prevention.

Dr. Cathy Tangen, a member of SWOG, leads the biostatistics core for the grant, which is housed at the Hutchinson Center. Core team members include SWOG's Phyllis Goodman, lead statistician on the PCPT, and Drs. Michael LeBlanc, Mary Redman and John Crowley, who is also the president and chief executive officer of Cancer Research and Biostatistics, and serves as a co-principal investigator.

The current project takes advantage of the careful design, comprehensive biorepository and unusually large size of the PCPT, which tested the hypothesis that administration of the drug finasteride would reduce the prevalence of prostate cancer. Participants provided blood samples throughout the study and a biopsy at the end — excellent material for further study. "First, we have a definitive diagnosis of prostate cancer, because all men underwent prostate biopsy," Kristal said. "Second, we have a biorepository consisting of prostate tissue and eight years of annual blood samples from all of the participants. Lastly, we have an extraordinarily talented and hard-working group of scientists who are committed to working together to integrate findings across the PO-1 projects."

Five areas of focus

The study is divided into five separate but overlapping projects. Areas of focus include the roles of androgen metabolism; diet and diet-related factors; insulin-like growth factors and insulin resistance; inflammation; and oxidative damage and DNA repair in the development of prostate cancer.

Dr. Irena King, PHS staff scientist, heads a lab measuring serum micronutrients as one component of the diet study. Dr. Marian Neuhouser, also a PHS staff scientist, is co-principal investigator with Dr. Michael Pollak, of McGill University in Montreal, in the studies of insulin-like growth factors and insulin resistance.

The projects will examine samples from 1,800 men who developed prostate cancer during the course of the PCPT study. Also included are samples from 1,800 men who did not develop cancer who were frequency matched to cancer cases by age and family history of prostate cancer. Because non-Caucasian populations were under represented in the PCPT, most samples from these populations will be used to maximize the ability to address questions specific to race.

Now in their first year of funding, the researchers are setting up infrastructure, conducting pilot studies and determining which external laboratories will be involved in analyses. Work is already under way on the diet-related factors study, which draws in part from food-frequency surveys filled out by the participants and measures of weight and body circumferences, as well as from micronutrients measured in serum.

"I've already discovered some very interesting associations of obesity with prostate-cancer risk, which resolve some of the inconsistencies from other previous studies with less statistical power," said Kristal, who leads the diet study. "As we start to run tissue and serum-based assays, the science will become enormously exciting."

Investigators participate in monthly conference calls and meet twice yearly to coordinate among the multiple institutions involved in the study. While the logistics of such a collaborative endeavor could easily overwhelm, Kristal describes the dynamics as "overall, just great. So far, everyone has the good of the project as their first priority, and all hard decisions have gone well."

PCPT: Shedding light on more than prostate cancer

In addition to helping improve understanding of prostate cancer, data collected during the Southwest Oncology Group's (SWOG) original Prostate Cancer Prevention Trial (PCPT) recently generated insights into risk factors for heart disease. Analysis of data led to the discovery that even after adjusting for the effects of traditional risk factors, men with erectile dysfunction (ED) had a 45 percent greater risk of a cardiovascular event compared to those without ED. This suggests that ED is at least as important in predicting heart disease as smoking, activity level or family history.

Dr. Ian Thompson of the University of Texas Health Science Center led the study, which also included Drs. Catherine Tangen and Carol Moinpour, of SWOG; Phyllis Goodman, lead biostatistician of the PCPT; and Dr. Jeffrey Probstfield of the University of Washington. Results appeared in the Dec. 21, 2005, edition of the Journal of the American Medical Association.

Thompson and his team used data collected on questionnaires during the PCPT to test the hypothesis that impotence could serve as a predictive factor, or sentinel symptom, for heart disease. They analyzed data on more than 8,000 men from the placebo arm who entered the PCPT with no heart disease. Forty-seven percent of these men had a history of ED at the study's outset. After five years, 57 percent of those with no ED at study entry had experienced some degree of ED.

Results of several analyses conducted by Thompson and his colleagues concurred; sexual dysfunction is a strong predictor of cardiovascular disease, particularly angina, myocardial infarction and stroke. Men who entered the study with no sign of sexual dysfunction were calculated to have a 1.5 percent risk of a cardiovascular event for each year that they didn't have ED. Once men reported having ED, their risk of a cardiovascular event increased to 2.4 percent per year. This increase in vulnerability to cardiovascular disease is considerable. Thompson and colleagues calculated it to be similar to increased risk associated with smoking or family history of heart attacks.

Heart disease is the leading cause of death for Americans. Further, 50 percent of men who die from heart attacks show no prior symptoms of heart disease. For these reasons, the identification of a powerful new predictive tool could be enormously useful. Thompson and colleagues hope that health care providers will use symptoms of sexual dysfunction as a red flag, prompting further investigation into risk factors for cardiovascular disease and potentially behavioral and/or pharmacological interventions.